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The Role of Poly (Adenosine 5'-Diphosphate-Ribose) Polymerase in the Response of Pituitary Tumor Cells to Reactive Oxygen Species

Max-Plank-Institute of Psychiatry, Neuroendocrinology Group, D-80804 Munich, Germany

Address all correspondence and requests for reprints to: Dr. Ulrich Renner, Max-Planck-Institute of Psychiatry, Neuroendocrinology Group, Kraepelinstr. 10, D-80804 Munich Germany. E-mail: renner{at}mpipsykl.mpg.de.

As an enzyme implicated in the stress response, we investigated poly(ADP-ribose) polymerase (PARP) in the response of GH₃ rat pituitary tumor cells to oxidants. These cells are unusual in that they undergo rapid cell death (90 min) with low doses of the prooxidant, H₂O₂ (50–200 µM), whereas at higher doses (1 mM), death occurs some hours later (4–5 h). Measurement of PARP activity shows that low doses of H₂O₂ (50–200 µM) fail to increase the activity of PARP, whereas at 0.5 and 1 mM, the enzyme becomes activated. In parallel with the activation of PARP, cellular ATP concentrations fall at high H₂O₂ doses and the PARP inhibitors, 3-aminobenzamide and nicotinamide (NIC) partially prevent this fall. Using NIC to inhibit PARP activity, we show that treatment of cells with NIC before the addition of H₂O₂ (0.5–1 mM), results in rapid cell death (90 min). In contrast, prior exposure to H₂O₂ (0.5–1 mM) for 1 h, before withdrawal and exposure to 1 mM NIC, allows cell survival for many hours. These data suggest that PARP is involved in blocking rapid death of GH₃ cells in response to oxidants. In contrast to other cell types tested here, in which inhibitor studies show that PARP is activated at low H₂O₂ doses and this decreases the extent of apoptosis, GH₃ cells are unable to sufficiently activate PARP to prevent rapid cell death.